|
INTRODUCTION |
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Background: Human
papillomaviruses (HPVs) produce epithelial tumors of the skin and mucous
membranes. Over 100 HPV types have been detected, and the genomes of almost 70
have been sequenced completely. The current classification system, which is
based on similarities in their genomic sequences, generally correlates with the
3 categories used to describe HPV clinically: anogenital and/or mucosal,
nongenital cutaneous, and epidermodysplasia verruciformis (EV). A database of
HPV genomic sequences and a phylogenic tree are available via the Internet at,
HPV Sequence Database.
The mucosal HPV infections are classified further as latent (asymptomatic),
subclinical, or clinical. Clinical lesions are grossly apparent, whereas latent
infections are detected only by tests for viral DNA. Subclinical lesions are
identified by application of 5% acetic acid and inspection under magnification.
Most HPV infections are latent; clinically apparent infections usually result in
warts rather than malignancies.
HPV types 6 and 11 typically are labeled as low risk because infection with
these types has low oncogenic potential and usually results in the formation of
condylomata and low-grade precancerous lesions. HPV types 16 and 18 have emerged
as the high-risk types of HPV because they are responsible for most high-grade
intraepithelial lesions that may progress to carcinomas, particularly those in
the anogenital and/or mucosal category.
HPV infection alone is not enough to cause malignant transformation of
infected tissue. Cofactors, such as tobacco use, ultraviolet radiation,
pregnancy, folate deficiency, and immune suppression have been implicated in
this process. The table lists a variety of diseases and the associated HPV
subtypes.
Diseases and Associated HPV Subtypes
| Nongenital Cutaneous Disease |
HPV Type |
Common warts (verrucae vulgaris)
Warts (Nongenital) |
1, 2, 4, 26, 27, 29, 41, 57, 65 |
Plantar warts (myrmecias)
Warts,
Plantar |
1, 2, 4, 63 |
| Flat warts (verrucae plana) |
3, 10, 27, 28, 38, 41, 49 |
| Butcher’s warts (common warts of people who handle meat, poultry, and
fish) |
1, 2, 3, 4, 7, 10, 28 |
| Mosaic warts |
2, 27, 57 |
| Ungual squamous cell carcinoma |
16 |
Epidermodysplasia verruciformis (benign)
Epidermodysplasia Verruciformis |
2, 3, 10, 12, 15, 19, 36, 46, 47, 50 |
Epidermodysplasia verruciformis (malignant or benign)
Epidermodysplasia Verruciformis |
5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38 |
| Nonwarty skin lesions |
37, 38 |
| Nongenital Mucosal Disease |
HPV Type |
Respiratory papillomatosis
Recurrent
Respiratory Papillomatosis |
6, 11 |
| Squamous cell carcinoma of the lung |
6, 11, 16, 18 |
| Laryngeal papilloma |
6, 11, 30 |
| Laryngeal carcinoma |
16, 18 |
| Maxillary sinus papilloma |
57 |
| Squamous cell carcinoma of the sinuses |
16, 18 |
| Conjunctival papillomas |
6, 11 |
| Conjunctival carcinoma |
16 |
| Oral focal epithelial hyperplasia (Heck disease) |
13, 32 |
| Oral carcinoma |
16, 18 |
| Oral leukoplakia |
16, 18 |
| Squamous cell carcinoma of the esophagus |
16, 18 |
| Anogenital Disease |
HPV Type |
| Condylomata acuminata |
6, 11, 30, 42, 43, 44, 45, 51, 52, 54 |
Bowenoid papulosis
Bowenoid
Papulosis |
16, 18, 34, 39, 42, 45 |
| Bowen disease |
16, 18, 31, 34 |
Giant condylomata (Buschke-Löwenstein tumors)
Giant
Condylomata Acuminata of Buschke and Löwenstein |
6, 11 |
| Unspecified intraepithelial neoplasia |
30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69 |
| Low-grade intraepithelial neoplasia |
6, 11, 43 |
| Intermediate intraepithelial neoplasia |
31, 33, 35, 42, 44, 45, 51, 52 |
| High-grade intraepithelial neoplasia |
16, 18, 56, 58 |
Carcinoma of vulva
Malignant
Vulvar Lesions |
6, 11, 16, 18 |
| Carcinoma of vagina |
16 |
Carcinoma of cervix
Cervical
Cancer |
16, 18, 31 |
| Carcinoma of anus |
16, 31, 32, 33 |
| Carcinoma in situ of penis (erythroplasia of Queyrat) |
16 |
| Carcinoma of penis |
16, 18 |
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Pathophysiology: Papillomaviruses are highly species
specific and do not infect other species, even under laboratory conditions.
Humans are the only known reservoir for HPV. Papillomaviruses are nonenveloped
viruses of icosahedral symmetry with 72 capsomeres that surround a genome
containing double-stranded circular DNA with approximately 8000 base pairs.
Papillomaviruses are thought to have 2 modes of replication—stable replication
of the episomal genome in basal cells and runaway, or vegetative, replication in
more differentiated cells to generate progeny virus. Although all cells of a
lesion contain the viral genome, the expression of viral genes is linked tightly
to the state of cellular differentiation. Most viral genes are not switched on
until the infected keratinocyte leaves the basal layer. Production of virus
particles can occur only in highly differentiated keratinocytes; therefore,
virus production only occurs at the epithelial surface where the cells are
ultimately sloughed into the environment.
HPV lesions are thought to arise from the proliferation of infected basal
keratinocytes. Infection typically occurs when basal cells are exposed to
infectious virus through a disturbed epithelial barrier as would occur during
sexual intercourse or after minor skin abrasions. HPV infections have not been
shown to be cytolytic, rather viral particles are released as a result of
degeneration of desquamating cells. The HPV virus can survive for many months
and at low temperatures without a host; therefore, an individual with plantar
warts can spread the virus by walking barefoot.
Virus multiplication is confined to the nucleus. Consequently, infected cells
exhibit a high degree of nuclear atypia. Koilocytosis (from the Greek koilos,
meaning empty) describes a combination of perinuclear clearing (halo) with a
pyknotic or shrunken (rasinoid) nucleus and is a characteristic feature of
productive papillomavirus infection.
The HPV genome exists as a circular, episomal DNA separate from the host cell
nucleus in benign or low-risk HPV lesions, such as those typically associated
with HPV types 6 and 11. The genomes of high-risk HPV types 16 and 18 typically
are integrated into the host cell DNA in malignant lesions. Integration of the
viral genome into the host cell genome is considered a hallmark of malignant
transformation. HPV proteins E6 and E7 of high-risk serotypes have been shown to
inactivate the host's tumor suppressor proteins p53 and Rb, thereby resulting in
unregulated host cell proliferation and malignant transformation.
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Frequency:
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- In the US: The number of patients identified with HPV
disease has increased markedly during the past 20 years due to heightened
awareness of the various manifestations of HPV disease and to increased use of
HPV DNA testing.
Patients receiving immunosuppressive drugs and patients with defects in
cell-mediated immunity, including those infected with the human
immunodeficiency virus (HIV), are especially susceptible to developing HPV
infections.
In the US, 2.5 million women are estimated to have an annual cytological
diagnosis of a low-grade cervical cancer precursor.
The incidence of
Cervical
Cancer has decreased dramatically during the last century due to
implementation of the
Pap Test
beginning in the 1930s and 1940s. However, from 1990 to 2001 the annual number
of estimated new invasive cervical cancers has remained relatively constant
from a total of 13,500 to 12,900, respectively.
Anogenital warts, or condylomata acuminata, are the most commonly diagnosed
viral sexually transmitted disease (STD) in the US and the United Kingdom. The
annual incidence is estimated to be between 500,000 and 1 million cases. From
1966-1986, the incidence of genital warts has increased 5-fold.
Approximately 7-10% of the population has nongenital cutaneous warts.
- Internationally: The worldwide prevalence of HPV in
cervical carcinoma is 95 to 99.7% and in anal cancer is 88%.
In many lesser-developed countries, cervical cancer is the most common
cancer among women due to the lack of effective screening programs that
monitor cervical cytology by Pap smear.
In many developing nations cervical cancer is the leading cause of cancer
mortality among women. Worldwide, it is the second most common cause of cancer
mortality among women.
Mortality/Morbidity:
- Anogenital/mucosal disease: A direct correlation exists between anogenital
HPV infection and measures of sexual activity, such as the age of first
intercourse and the lifetime number of sexual partners. Women with a history
of a cervical high-grade squamous intraepithelial lesion (HGSIL) or invasive
squamous cell carcinoma (SCC) of the cervix are at increased risk for
subsequent development of invasive cancer in other tissues of the anogenital/mucosal
category, particularly vaginal and anal carcinoma. In these patients, the
relative risk of vaginal carcinoma is 5.6, and risk of anal carcinoma is 4.
Anal cancer has been associated strongly with male homosexuality and specific
male practices, such as engaging in receptive anal intercourse. Relative risk
is 33. The overall disease prevalence, however, is higher in women than in
men, with a female-to-male ratio of 1.5:1.
- Nongenital cutaneous warts: Cutaneous lesions typically produce benign,
self-limited warts (see
Warts [Nongenital]).
- Epidermodysplasia verruciformis: Patients who are immunosuppressed,
particularly those with cutaneous malignant lesions, have a much higher
incidence of EV-HPV infection than the general population. These lesions can
undergo malignant transformation. Ten percent of patients with EV originate
from consanguineous marriages, suggesting an autosomal recessive mode of
inheritance (see
Epidermodysplasia Verruciformis).
Race:
- From 1987?991, the age-adjusted
Cervical
Cancer death rate reported by the US National Cancer Institute was higher
among African American women compared to white women, with a ratio of 6:1.
- Nongenital cutaneous warts are more common in whites than in people of
African descent.
Sex:
- The overall prevalence of HPV in women is 22?5%.
- In men, the prevalence is 2-35% depending on the sexual practices of the
population being studied.
Age:
- Anogenital mucosal HPV infections are highest among college-aged women and
men.
- Nongenital cutaneous warts are more common among teenagers and adults who
work as meat, poultry, and fish handlers. The incidence approaches 10% in the
child and young adult populations. However, nongenital cutaneous warts rarely
occur in people younger than 5 years and usually regress within 2 years.
- EV develops at an average age of onset of 6 years, and, beginning in the
fourth decade, the lesions can undergo malignant transformation into invasive
SCC.
|
|
CLINICAL |
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History:
- Condylomata acuminata are exophytic cauliflowerlike lesions that usually
are found near moist surfaces. They may be observed in the perianal area,
vaginal introitus, vagina, labia, and vulva. Genital warts also may be found
on dry surfaces, such as the shaft of the penis.
- Genital warts include smooth papular warts and keratotic warts, the
latter of which resemble nongenital cutaneous warts due to their thickened,
bumpy surface.
- Genital flat warts are subclinical lesions that typically appear on the
cervix. Colposcopic examination with 3% acetic acid solution is required for
identification.
- Most cervical infections are either latent or subclinical and, as such,
are asymptomatic. These infections will be detected on Pap tests and
reported as either a low-grade squamous intraepithelial lesion (LGSIL) or a
high-grade squamous intraepithelial lesion (HGSIL). Further examination with
3-5% acetic acid and colposcopy shows characteristic acetowhite changes and
abnormal blood vessels indicative of HPV-triggered dysplasia.
- Patients who have neglected to obtain annual Pap testing for several
years or more and who have a HGSIL that has progressed to invasive cancer of
the cervix may complain of vaginal bleeding between periods, dyspareunia,
and fullness in their pelvis.
- The most common presenting symptoms of SCC of the anus are rectal
bleeding and sensation of a mass. This may be attributed mistakenly to
hemorrhoids.
- Fifty percent of men who are homosexual and have SCC of the anus will
have a history of anorectal warts; however, only 20% of women with SCC and
men who are not homosexual will have this history.
- Nonanogenital mucosal disease
- HPV types 6 and 11 have been isolated on nonanogenital mucosal surfaces.
Warts have been discovered in the nares, mouth, larynx, and conjunctiva.
- HPV types 6 and 11 are associated with respiratory papillomas that
likely are the result of intrapartum transmission of the infant through the
birth canal of a mother who is infected with HPV. However, isolated case
reports exist of respiratory papillomatosis after Cesarean Section.
Laryngeal papillomas occur at an average age of 3 years, presenting most
frequently with a complaint of hoarseness.
- Cutaneous lesions typically produce benign, self-limited warts.
- Deep plantar warts occur most commonly as solitary lesions that may
become black and painful prior to spontaneous regression. They may contain
small black seeds, which represent thrombosed capillaries.
- Common warts can occur on any skin surface but usually are found on the
hands and fingers. They appear as skin-colored exophytic rough papules and
nodules that have minimal scaling. Autoinoculation from a wart on one finger
may cause the occurrence of warts on an adjacent finger or other skin
surface, so-called kissing warts.
- Warts that occur in people who handle meat and fish often have large
cauliflowerlike plaques.
- Flat warts most often occur in groups of small plaques less than 5 mm in
diameter on the face and hands. Regression usually occurs spontaneously
after several years, and pruritus or erythema occur several weeks prior to
their disappearance.
- Epidermodysplasia verruciformis
- The malignant conversion of skin lesions usually begins in the fourth
and fifth decades of life. Premalignant lesions usually first arise on the
forehead and other sun-exposed areas. The tumors are either benign
papillomas and seborrheic keratoses or premalignant actinic keratoses and
SCC.
- EV tumors are locally destructive. They develop slowly and have weak
metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B
irradiation, are applied. Polymorphic, plane wartlike, and red-to-brownish
plaques can be distributed widely over the skin. The lymph nodes and oral
mucosa are not involved.
Physical: The findings on physical exam depend on the
tissues involved. They include a variety of cutaneous lesions with
characteristic appearances noted above. Figures 1 through 4 demonstrate
extensive anogenital condyloma acuminatum.
Causes:
- Types of HPV demonstrate a high degree of site specificity, with some HPV
types only found on certain parts of the skin or mucous membranes.
- HPV infection alone is not enough to cause malignant transformation of
infected tissue. Cofactors, such as tobacco use, ultraviolet radiation,
pregnancy, folate deficiency, and immune suppression, have been implicated in
this process. Patients receiving immunosuppressive drugs and patients with
defects in cell-mediated immunity, including those infected with HIV are
especially susceptible to developing HPV infections.
- A direct correlation exists between anogenital HPV infection and measures
of sexual activity, such as the age of first intercourse and the lifetime
number of sexual partners.
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|
DIFFERENTIALS |
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Benign Cervical Lesions
Benign Vulvar Lesions
Carbon Dioxide Laser
Surgery of the Lower Genital Tract
Cervical Cancer
Conization of Cervix
Gynecologic Cryosurgery
Hemorrhoids
Hidradenitis Suppurativa
Malignant Vulvar Lesions
Molluscum Contagiosum
Penile Cancer
Recurrent Respiratory
Papillomatosis
Surgical Treatment of
Vaginal Cancer
Surgical Treatment of
Vulvar Cancer
Urethral Warts
¡@
Other Problems to be Considered:
Actinic keratoses
Carbon dioxide laser surgery for intraepithelial cervical neoplasms
Cervical polyp
Condyloma lata
Dermatitis papillaris
Nevi
Oropharyngeal SCC
Pityriasis versicolor
Sinonasal
Papillomas, Treatment
Warts (Nongenital)
Pap Test
Recurrent
Respiratory Papillomatosis
Squamous Cell
Carcinoma
Warts,
Plantar
Bowenoid
Papulosis
Warts
Epidermodysplasia Verruciformis
Squamous Cell
Carcinoma, Eyelid
Warts
(Genital)
Giant
Condylomata Acuminata of Buschke and Löwenstein
Acanthosis
Nigricans
Acrochordon
Corns and
Calluses
Keloid and
Hypertrophic Scar
Keratoacanthoma
Lichen Planus
Psoriasis
(Plaque)
Seborrheic
Keratosis
Malignant
Tumors of the Mobile Tongue
|
|
WORKUP |
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Lab Studies:
¡@
- Cervical cytologic testing using the Pap test is the standard screening
procedure for cervical neoplasia. It should be performed annually on all
women once they become sexually active or when they have reached the age of
18 years if they have remained abstinent. Once a woman has had 3 or more
consecutive annual Pap tests that are within normal limits, the Pap test may
be performed less frequently if the patient is at low risk for developing
cervical dysplasia.
- Pap tests should contain samples of cells from the ectocervix,
transformation zone, and endocervical canal. Perform the test when the
patient is not menstruating so that the cytologic specimen is not occluded
with blood. Furthermore, if the patient has a cervicovaginal infection with
a mucopurulent vaginal discharge, consider performing the test after the
bacterial infection has resolved. If the test must be performed, the
discharge should be cleared gently with a saline-moistened cotton swab.
- This test may be modified as required to sample tissues of the vagina,
vulva, or perianal region that are suspicious for intraepithelial neoplasia.
Although not an established routine, consider performing annual anal Pap
tests on men who have high risk and who participate in receptive anal
intercourse.
- See
Cervical
Cancer for guidelines on how often to perform the Pap test when
abnormalities result.
- HPV DNA typing using polymerase chain reaction (PCR) methods may be used
to help clarify the diagnosis if doubt exists about the cause of a lesion.
- This modality also may be used to help guide management by
distinguishing between high- and low-risk types of HPV. However, little data
exists to support the routine use of this modality.
- Tissue biopsy can be used to confirm HPV infection if the diagnosis is
uncertain, particularly if warts are abnormally pigmented, ulcerated, or
indurated.
- Obtain a biopsy of a warty lesion if the patient is immunocompromised,
if the lesions worsen during treatment, or if they do not respond to
standard therapy.
Histologic Findings: Virus multiplication is confined to the
host cell nucleus. Consequently, infected cells exhibit a high degree of nuclear
atypia. Koilocytosis describes a combination of perinuclear clearing with a
pyknotic or shrunken nucleus and is a characteristic feature of productive
papillomavirus infection. Other cytologic markers of HPV infection include
acanthosis, dyskeratosis, and multinucleation.
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|
TREATMENT |
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Medical Care:
General introduction
Removal or reduction of symptoms is the primary goal of treating warts, but
elimination of dysplastic lesions is the goal in treating squamous
intraepithelial lesions (SILs). Treatment is not recommended for subclinical
anogenital and/or mucosal HPV infection in the absence of coexistent dysplasia.
No evidence demonstrates that treatment will eliminate HPV infection or that it
will decrease infectivity. In fact, warts may recur after treatment due to
activation of latent virus present in normal skin adjacent to the lesion.
No single treatment modality has been demonstrated to be superior, nor is one
modality ideal for all types of warts. Factors that influence treatment of HPV
disease include the size, morphology, number, and anatomic site of lesions, as
well as cost, adverse effects, patient preference, and provider experience.
Most patients with warts will require multiple treatments over a course of
several weeks or months. If substantial improvements are not present after 3
physician-administered treatments or if complete clearance has not occurred
after 6 treatments, a different treatment modality should be used.
Introduction to medical treatment
All medicines used to treat HPV disease are applied topically on cutaneous
surfaces. Local skin reactions and pain are common adverse effects. Do not apply
any of these medications to mucosal surfaces and do not use them to treat
dysplastic lesions, SCC, verrucous carcinomas, or
Bowenoid
Papulosis.
Two broad categories of medications are effective in treating HPV disease.
The first category, the immune response modifiers (ie, imiquimod, interferon
alpha), is used primarily in treatment of external anogenital warts or
condylomata acuminata. The second category consists of the cytotoxic agents,
which include the antiproliferative drugs podofilox, podophyllin, and
5-fluorouracil, as well as the chemodestructive or keratolytic agents salicylic
acid, trichloroacetic acid (TCA), and bichloroacetic acid (BCA).
None of these medicines has been shown to be uniformly effective or directly
antiviral. The keratolytics are the only agents that are recommended for
treatment of nongenital cutaneous warts.
- This immune response modifier has no direct antiviral activity; however,
it is a powerful cytokine inducer, which stimulates production of interferon
alpha, tumor necrosis factor, and interleukin (IL)-1, IL-6, and IL-8.
- This patient-applied treatment is used for the treatment of external
anogenital warts and condyloma acuminatum. It should be applied 3 times per
week, with application approximating an every-other-day routine (eg, Monday,
Wednesday, Friday). Remove the cream by washing with mild soap and water
6-10 hours after application.
- Treatment should continue until the warts have completely cleared, up to
a maximum of 16 weeks.
- Local skin reactions are common, especially following contact with
mucosal surfaces.
- This naturally occurring cytokine is produced by recombinant DNA
technology or by collection from pooled human leukocytes. It has potent
immunomodulatory, as well as direct antiviral, effects.
- This physician-applied medicine is used for intralesional treatment of
external anogenital warts and condyloma acuminatum. It should be injected
into the base of each wart, preferably using a 30-gauge needle. For large
warts, it may be injected at several points around the periphery of the
wart, using a total dose of 250,000 IU per wart. Direct the needle at the
center of the base of the wart and at an angle almost parallel to the plane
of the skin (approximating that in the commonly used purified protein
derivative [PPD] test).
- The maximum response usually occurs 4-8 weeks after initiation of the
first treatment course. If results at 12-16 weeks following the initial
treatment course with interferon alpha-2b are not satisfactory, a second
course of treatment using the same dosage schedule may be instituted,
providing that clinical symptoms and signs or changes in laboratory
parameters (liver function tests, WBC, platelets) do not preclude such a
course of action.
- Patients with 6-10 condylomata may receive a second (sequential) course
of treatment using the same dosage schedule to treat up to 5 additional
condylomata per course of treatment. Patients with more than 10 condylomata
may receive additional sequences depending on how many condylomata are
present.
- Podofilox
¡@
- This antimitotic drug is either chemically synthesized or purified from
naturally occurring podophyllin resin. Application stimulates visible
necrosis of wart tissue.
- This patient-applied medicine is used in the treatment of external
genital warts or condyloma acuminatum. It is applied twice a day for 3 days,
followed by 4 days of no therapy. This cycle can be repeated for a maximum
of 4 cycles.
- To ensure that the patient is fully aware of the correct method of
therapy and to identify which specific warts should be treated, the
prescriber should demonstrate the technique for initial application of the
medication.
- No more than 0.5 g of gel per day should be used. Limit the total wart
tissue treated to 10 cm2 or less.
- Podophyllin
¡@
- This resin derived from the Mayapple (Podophyllum peltatum Linn?/em>)
contains the active agent podophyllotoxin, which is a cytotoxic agent that
arrests mitosis in metaphase.
- Podophyllin is a physician-applied medicine used in the treatment of
external genital warts and condyloma acuminatum. It can be applied weekly
for up to 6 weeks.
- Prior to application, thoroughly cleanse the affected area. Avoid
contact with healthy tissue. Apply the medicine sparingly and allow to dry
thoroughly.
- Initial application should be for 30-40 minutes. Subsequent applications
can be for 1-4 hours. Remove dried podophyllin with alcohol or with soap and
water. Do not treat large areas or numerous warts at once.
¡@
- 5-fluorouracil
- This antimetabolite interferes with the synthesis of DNA and RNA. This
action creates a thymine deficiency, resulting in unbalanced growth and
death of a cell.
- This patient-applied treatment is not formally indicated for treatment
of HPV disease; however, the 5% cream formulation can be helpful in the
treatment of some genital warts. It is applied 1-3 times per week for
several weeks as needed.
- Prior to application, thoroughly cleanse the affected area. Avoid
contact with healthy tissue. Apply the medicine sparingly and allow to dry
thoroughly. Remove dried cream 3-10 hours after application.
¡@
- Keratolytics
¡@
- TCA and BCA are extremely powerful keratolytic agents that rapidly
penetrate and chemically cauterize skin, keratin, and other tissues. The
cauterizing effect is comparable to cryotherapy or electrodesiccation. These
physician-applied agents can be used on all types of cutaneous warts.
¡@
- An 80-90% solution is applied directly on a weekly basis. As the acid
dries, a white frosting develops and should be powdered with sodium
bicarbonate to remove any unreacted acid.
¡@
- Salicylic acid is a milder keratolytic that typically is purchased in
nonprescription formulations. This patient-applied medicine is used
primarily to treat nongenital cutaneous warts.
Surgical Care: Various surgical techniques are available for
the treatment of HPV disease. With the exception of cryosurgery, these
modalities usually have the common advantage of complete treatment following one
application. However, surgical modalities typically require local anesthesia and
more time and equipment to implement. Consequently, they often are used when a
large number or area of warts is present or on patients with refractory disease.
Furthermore, recurrence of HPV disease is less common following surgical
treatment as opposed to medical therapy.
Primary surgical therapy often can be accomplished in the office and includes
cryosurgery, electrosurgery with either electrodesiccation or loop
electrosurgical excision procedure (LEEP), or simple surgical excision with a
scalpel, scissors, or curette.
Alternative surgical procedures requiring more advanced equipment and
training include carbon dioxide laser ablation, Cavitron ultrasonic surgical
aspiration (CUSA), or Mohs surgery.
- This physically ablative method is a rapid and effective means of
treating simple HPV disease. It works by freezing the intracellular water,
resulting in cellular destruction.
- Although it is somewhat painful, local anesthesia typically is not used.
After 2-4 treatments in a 6- to 12-week period, 75-80% of patients will
experience a complete clearing of warts.
- This method is effective for most simple cutaneous warts and for
low-grade cervical intraepithelial neoplasia (CIN I). It is not recommended
for use in the vagina because the depth of ablation cannot be controlled and
damage to adjacent structures, such as the bladder and rectum, is possible.
¡@
- Liquid nitrogen is applied to the wart using a cotton-tipped applicator,
a cryoprobe, or a fine spray. Gases, such as nitrous oxide and carbon
dioxide, also can be used.
- The freeze-thaw-freeze method is thought to be more effective than a
single freeze. Application is continued until up to a 5-mm margin of
surrounding skin or mucosa is frozen. After the skin turns white, freezing
is continued for up to 30 seconds and then allowed to thaw. If the patient
can tolerate the pain, a second cycle is applied.
- Within 24 hours after treatment, a bulla forms over the treated area. An
additional course of treatment can be applied in 1-2 weeks as needed. This
treatment modality is safe for use in women who are pregnant because it is
not systemically absorbed.
- Electrosurgery
- These modalities use high-frequency current to cut and coagulate warts.
Electrodesiccation using a bipolar needle can be used to coagulate wart
tissue deeply. This is most effective against external genital warts.
- LEEP uses a bipolar loop to vaporize and fulgurate affected tissue. It
is used primarily to treat cervical SILs; however, it also may be used to
remove large external genital warts.
- Electrosurgical methods usually require only local anesthesia and may be
employed in an outpatient setting if the appropriate equipment is available.
- HPV DNA has been found in smoke plumes; therefore, procedures to
evacuate the smoke and prevent inhalation must be used.
- Surgical removal
- Simple surgical excision with a scalpel, scissors, or curette can be
performed under local anesthesia to remove warts and treat SILs of the
genital tract.
- Mohs surgery can be performed by specially trained dermatologists to
excise tissue in areas where maximum conservation is required. This method
uses dermatopathology in conjunction with conservative excision of malignant
lesions. It may be of particular assistance in managing verrucous
carcinomas.
- Carbon dioxide laser vaporization is an alternative surgical procedure
that typically is used for treatment of refractory HPV disease or extensive
warts of the anogenital/mucosal category. This precisely controlled modality
conserves normal adjacent tissue. It particularly is useful in treatment of
periurethral and vaginal warts and vaginal SILs.
- HPV DNA has been found in laser smoke plumes; therefore, procedures to
evacuate the smoke and prevent inhalation must be used.
- Cavitron Ultrasonic Surgical Aspirator (CUSA)
- This device vibrates at a frequency of 23 kHz, which is an order of
magnitude lower than the frequency of a diagnostic ultrasound. It destroys
tissue through heat and cavitation.
- CUSA has been used extensively for cytoreduction of intraabdominal
tumors because of the ability to remove epithelium without damage to
underlying tissue. Consequently, it has been employed as an alternative
therapy against extensive anogenital warts.
Consultations:
- Consult a gynecologic oncologist for assistance in management of genital
tract SILs and carcinomas, as well as exophytic cervical warts and giant
condylomata.
- Consult a urologist for assistance with surgical management of urethral
warts, penile condylomata, SILs, or carcinomas.
- Consult a colorectal surgeon for assistance with the surgical management
of perianal condylomata or anal SILs or carcinomas.
- Consult an otolaryngologist for assistance with management of
oropharyngeal papillomas or SCC.
- Consult a dermatologist in the following cases:
- Consult a dermatologist for assistance with management of EV.
- Bleeding warts, moles, birthmarks, or unusual warts with hair growing
from them can be confused with HPV disease. Refer these types of lesions to
a dermatologist for diagnostic clarification.
- Dermatologists who specialize in Mohs surgery, which uses
dermatopathology in conjunction with the conservative excision of malignant
lesions, may be of particular assistance in managing verrucous carcinomas.
- Consult an infectious disease specialist for assistance in management of
HPV disease in patients who are immunocompromised.
Diet: Folate deficiency is the only dietary factor that has
been shown to play a role in early cervical carcinogenesis. Folate deficiency
apparently facilitates incorporation of HPV DNA at a fragile chromosomal site,
thereby establishing a basis for malignant transformation.
Activity: Certain activities are associated with an
increased risk of HPV malignant transformation, particularly in the anogenital/mucosal
category.
- A direct correlation exists between anogenital HPV infection and
measures of sexual activity, such as the age of first intercourse and the
lifetime number of sexual partners.
- Women with a history of cervical HGSIL or invasive SCC of the cervix are
at increased risk for subsequent development of invasive cancer in other
tissues of the anogenital/mucosal category, particularly vaginal and anal
carcinoma, with relative risks of 5.6 and 4 respectively.
- Anal cancer has been strongly associated with male homosexuality and
with specific male practices, such as engaging in receptive anal
intercourse; relative risk is 33. The overall disease prevalence, however,
is higher in women than men, with a female-to-male ratio of 1.5:1.
- Women who smoke tobacco have an increased risk of developing cervical
neoplasia.
- Measurable amounts of a potent carcinogen, as well as several compounds
from cigarette smoke, have been identified in the cervical mucous of female
smokers. These agents are likely to play a role in the increased prevalence
of HPV malignant transformation of patients who smoke tobacco.
- Oral contraceptive use
- Women who use oral contraceptives for longer than 5 years have an
increased relative risk of developing cervical carcinoma.
- This risk declined after stopping oral contraceptives, and no risk was
demonstrated in users of less than 5 years duration.
- Chewing Indian betel quid
- A high incidence of oral cancer associated with HPV infection has been
demonstrated in India among patients who chew betel quid.
- This stimulant is made from the leaves of the betel plant and is used in
a manner similar to chewing tobacco.
¡@
- Ultraviolet and x-ray irradiation: EV is particularly susceptible to UV
and x-ray irradiation; therefore, patients with EV should avoid activities
that unnecessarily expose them to these forms of radiation.
|
|
MEDICATION |
¡@ |
The goals of pharmacotherapy are to reduce
morbidity and prevent complications.
¡@
Drug Category: Immune response modifiers -- These
agents have immunomodulatory effects and are used for treatment of external
anogenital warts or condyloma acuminatum.
Drug Name
¡@ |
Imiquimod (Aldara) -- Induces secretion
of interferon alpha and other cytokines. Mechanisms of action are unknown.
|
| Adult Dose |
Apply 3 times per wk, leave on skin for
6-10 h, remove by washing; treatment not to exceed 16 wk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity |
| Interactions |
None reported |
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks. |
| Precautions |
Not recommended for treatment of
rectal, cervical, intravaginal, urethral, and intraanal HPV infection;
following surgery or drug treatment, do not use until genital/perianal
tissue is healed; avoid sexual (genital, anal, oral) and eye contact while
the cream is on the skin; may weaken vaginal diaphragms and condoms,
concurrent use is not recommended |
Drug Name
¡@ |
Interferon alpha-n3 (Alferon N) and
interferon alpha-2b (Intron A) -- Protein product manufactured from either a
single-species recombinant DNA process or from pooled units of donated human
leukocytes that have been induced by incomplete infection with a murine
virus. Mechanisms by which it exerts antiviral activity are not understood
clearly. However, modulation of the host immune response may play an
important role. Indicated for intralesional treatment of refractory or
recurring external condyloma acuminatum. Particularly useful for patients
who have not responded satisfactorily to other treatment modalities (eg,
podophyllin resin, surgery, laser, cryotherapy). |
| Adult Dose |
Interferon alpha-n3: 0.05 mL (250,000
IU) per wart, 2 times per wk for up to 8 wk; maximum recommended dose per
treatment session is 0.5 mL (2.5 million IU)
Interferon alpha-2b: 1 million IU injected into each lesion 3 times per wk
on alternate days for 3 wk; maximum recommended dose per treatment session
is 5 million IU
|
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity to mouse
IgG, egg protein, or neomycin |
| Interactions |
Potential risk of renal failure when
administered concurrently with interleukin-2; theophylline may increase
toxicity by reducing clearance; cimetidine may increase antitumor effects;
zidovudine and vinblastine may increase toxicity |
| Pregnancy |
C - Safety for use during pregnancy has
not been established. |
| Precautions |
Depression and suicidal ideation may be
adverse effects of treatment; infrequently, severe or fatal GI hemorrhage
has been reported; prior to initiation of therapy, perform tests to
quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cell,
and bone marrow hairy cells; monitor periodically (eg, monthly) during
treatment to determine response to treatment; if no response within 6 mo,
discontinue treatment; if a response occurs, continue treatment until no
further improvement is observed and laboratory parameters have been stable
for about 3 mo; not known whether continued treatment after that time is
beneficial; because the manufacturing process, strength, and type of
interferon (eg, natural human leukocyte interferon versus single-species
recombinant interferon) may vary for different interferon formulations,
changing brands may require a change in dosage (do not change interferon
product without considering these factors); fever and other flulike symptoms
associated with this product;
caution in debilitating medical conditions (eg, unstable angina,
uncontrolled congestive heart failure, chronic obstructive pulmonary
disease, diabetes mellitus with ketoacidosis, coagulation disorders, severe
myelosuppression, seizure disorders) |
Drug Category: Antimitotic agents -- Interfere with
mitosis. Many are chemotherapeutic agents. The drugs listed below are used
specifically for treatment of external anogenital warts or condyloma acuminatum.
Drug Name
¡@ |
Podofilox (Condylox) -- Topical
antimitotic that can be synthesized chemically or purified from plant
families Coniferae and Berberidaceae (eg, species of Juniperus and
Podophyllum).
Treatment results in necrosis of visible wart tissue. Exact mechanism of
action is unknown.
|
| Adult Dose |
0.5% gel or solution applied to
anogenital warts bid for 3 consecutive d, then discontinue; repeat cycle
until no visible wart tissue or maximum of 4 cycles |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity |
| Interactions |
None reported |
| Pregnancy |
C - Safety for use during pregnancy has
not been established. |
| Precautions |
Avoid contact with eyes; if eye contact
occurs, immediately flush eye with copious quantities of water and seek
medical advice; not for use on mucous membranes of genital area, including
urethra, rectum, and vagina; not to exceed frequency of application or
duration of usage |
Drug Name
¡@ |
Podophyllin (Podocon-25, Podofin) --
Derived from Mayapple (Podophyllum peltatum Linn?/em>) and contains the
active agent podophyllotoxin, which is a cytotoxic agent that arrests
mitosis in metaphase. American podophyllum contains one-fourth the amount of
Indian source. |
| Adult Dose |
25% podophyllin in benzoin tincture is
applied only by a physician and is never dispensed to a patient; reapply
each wk for up to 6 wk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity, diabetes,
impaired peripheral circulation |
| Interactions |
None reported |
| Pregnancy |
X - Contraindicated in pregnancy |
| Precautions |
Powerful caustic and severe irritant;
do not use if surrounding tissue is swollen or irritated; do not apply 25%
solution near mucous membranes; do not use large amounts; avoid contact with
cornea (if contact occurs, flush with copious amounts of warm water); avoid
use on mucous membranes, eyes, bleeding warts, moles, birthmarks, or unusual
warts with hair |
Drug Category: Antimetabolites -- Interfere with
nucleic acid synthesis. Chemotherapeutic agents not formally approved for use
against warts. Some studies have demonstrated a benefit against external
anogenital warts or condyloma acuminatum.
Drug Name
¡@ |
Fluorouracil (Efudex) -- Interferes
with synthesis of DNA and RNA, which creates thymine deficiency resulting in
unbalanced growth and cell death. |
| Adult Dose |
5% strength applied as thin layer 1-3
times per wk; therapy may be required for up to 10-12 wk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity |
| Interactions |
None reported |
| Pregnancy |
X - Contraindicated in pregnancy |
| Precautions |
Incidence of inflammatory reactions may
occur with occlusive dressings; reports of vaginal ulcerations and vaginal
adenosis with clear cell carcinoma following treatment; not recommended for
treatment of vaginal condyloma; increased absorption through ulcerated or
inflamed skin; minimize ultraviolet irradiation exposure during and
immediately following treatment (reaction intensity may increase); only the
5% strength is recommended |
Drug Category: Keratolytics -- Used to aid in removal
of keratin in hyperkeratotic skin disorders including corns, ichthyoses, common
warts, flat warts, and other benign verrucae.
Drug Name
¡@ |
Trichloroacetic acid and bichloracetic
acid (TCA & BCA) -- Extremely powerful keratolytic agents that rapidly
penetrate and chemically cauterize skin, keratin, and other tissues. Can be
used to treat nongenital cutaneous warts, as well as external anogenital
warts or condyloma acuminatum. |
| Adult Dose |
80-90% solution applied directly by a
physician per wk |
| Pediatric Dose |
Administer as in adults |
| Contraindications |
Documented hypersensitivity |
| Interactions |
None reported |
| Pregnancy |
C - Safety for use during pregnancy has
not been established. |
| Precautions |
External use only; restrict use to
treatment areas only; avoid contact with eyes (if eye contact occurs,
immediately flush with copious quantities of water and seek medical advice);
not for use on premalignant or malignant lesions |
Drug Name
¡@ |
Salicylic acid (Compound W) -- By
dissolving the intercellular cement substance, salicylic acid produces
desquamation of the horny layer of skin, while not affecting structure of
viable epidermis. For removal of nongenital cutaneous warts, particularly
common or plantar warts.
Prior to application, wash affected area. May soak wart in warm water for 5
min. Dry area thoroughly.
|
| Adult Dose |
17% by weight solution or gel: Apply to
wart and let dry bid/tid as needed until wart is removed for up to 12 wk
40% by weight solution adsorbed to medicated discs: Apply over wart and
cover for 48 h, replace prn until wart is removed for up to 12 wk
|
| Pediatric Dose |
Administer as in adults |
| Contraindications |
Documented hypersensitivity |
| Interactions |
Use of this medication with other
topical drying agents (eg, tretinoin, sulfur, resorcinol, benzoyl peroxide)
or topical medicated or alcohol-containing preparations (eg, after shave,
toiletries, skin cleansers, cosmetics) may have a cumulative drying or
irritating effect leading to desquamation and skin erosion |
| Pregnancy |
C - Safety for use during pregnancy has
not been established. |
| Precautions |
Avoid contact with mucous membranes,
normal skin surrounding warts, and eyes; immediately flush with water for 15
min if contact with eyes or mucous membranes occurs; avoid inhaling vapors;
prolonged use in infants, people with diabetes, and patients with impaired
circulation is contraindicated; not for use on moles, birthmarks, warts with
hair growing from them, genital or facial warts, or warts on mucous
membranes, irritated skin, or any area infected or reddened |
|
|
FOLLOW-UP |
¡@ |
Complications:
¡@
- Complications of wart treatment are rare. Complications generally are
confined to the treatment site and include scarring and, in the case of
genital warts, vulvodynia or hyperesthesia.
- Surgical complications of treating SILs are discussed in the chapters
involving those diseases. See the following for discussion of complications:
Prognosis:
¡@
- Approximately two-thirds of patients with nongenital cutaneous warts will
experience a spontaneous regression within 2 years; however, some new warts
may appear.
- Most patients with EV experience progression of their disease in the third
or forth decade of life. Malignant transformation usually arises from actinic
keratoses, particularly in patients who are exposed to irradiation. Patients
who remain protected from x-rays and sun exposure generally have satisfactory
health.
- Genital warts may spontaneously regress, remain unchanged, or increase in
size. Treatment of these lesions does not affect the development of cervical
cancer.
- Histologic evidence of HPV infection on a cervical Pap test is similar to
mild dysplasia. This subclinical disease often spontaneously regresses.
Patient Education:
¡@
- Educating women, particularly those who are socially and economically
disadvantaged, about behaviors that enhance sexual risk reduction has a proven
benefit in reducing the incidence of STDs. Reducing the incidence of STDs
potentially could decrease HPV transmission and, consequently, the incidence
of cervical carcinoma.
|
|
MISCELLANEOUS |
¡@ |
Special Concerns:
¡@
- The risk of perinatal HPV transmission to the oropharyngeal mucosa of
the neonate is low both for mothers with latent infections or genital warts.
The time between rupture of the amnion and delivery may be a critical factor
in predicting transmission.
- Consider infants with HPV-positive nasopharyngeal aspirates in the
immediate postpartum period as contaminated rather than infected with HPV
because the virus generally clears from the neonate over several months
after birth. Cesarean section for the prevention of vertical HPV
transmission to the newborn is not indicated. In rare cases, however,
cesarean section may be indicated if the pelvic outlet is obstructed by
large genital warts.
- Although a high prevalence of HPV-associated penile SILs exists in the
male sex partners of women with cervical SILs, examination of these men is
not necessary for management of HPV disease. Nevertheless, sex partners of
patients with HPV disease may benefit from examination and a detailed
evaluation for STDs.
- Condom use may reduce the transmission of HPV to uninfected sex
partners, but it does not eliminate the risk. Furthermore, caution patients
that treatment does not eliminate the possibility of HPV transmission
because latent virus still may be present in tissues adjacent to treated
areas.
|
|
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